Connecting the dots

That was in the late 1980s and early 1990s when a drug called hydroxyethyl starch was first approved for use as a blood volume expander in North America.

Dr. Ryan Zarychanski.

At the time, both Canada and the United States were immersed in scandals resulting from people who had become infected with hepatitis C and HIV through improperly screened donor blood products. As a result, doctors on both sides of the border started to use hydroxyethyl starch, and agents like it, to increase the blood volume of patients awaiting a transfusion.

Jump forward to 2011. That's when Dr. Ryan Zarychanski decided to take a closer look at the benefits and risks of the product. And it is a good thing he and his medical research team did.

Zarychanski is an assistant professor in the Department of Internal Medicine at University of Manitoba's Faculty of Medicine and a clinician-scientist with CancerCare Manitoba. He is also Director of the Knowledge Synthesis platform at the George and Fay Yee Centre for Healthcare Innovation (CHI), which was created through a partnership between the University of Manitoba and the Winnipeg Health Region.

A hematologist and critical care physician by training, Zarychanski had frequently used hydroxyethyl starch to help patients in intensive care. Before products like hydroxyethyl starch were available, doctors would give critically ill patients salt solutions in combination with blood to restore blood pressure and enable the circulatory system to deliver oxygen to the body's organs and tissues. The development of hydroxyethyl starch helped reduce the reliance on blood for this purpose.

Yet while the blood volume expander was widely accepted and said to be "safe" by the companies that manufactured it, Zarychanski had his doubts. Over the years, he had heard polarizing opinions about the benefits and safety of hydroxyethyl starch from physicians he worked under during his specialty training in critical care and hematology.

As Zarychanski explains, the ability to properly resuscitate a critically ill patient amounts to a life-and-death scenario. As a result, defining best-practices under such circumstances is essential.

"Because of the variability in practice and opinion, and my own suspicion that these products were likely more harmful than many colleagues were prepared to admit, I felt it was critically important to study this topic further," he says.

To do so, Zarychanski employed a technique known in medical research circles as meta-analysis, a rigorous process designed to make sense of potentially conflicting information. He began his inquiry by enlisting the help of Dr. Ahmed Abou-Setta, a Research Associate at the CHI. Together, they pored over a multitude of studies on hydroxyethyl starch and other blood agents that had been done around the world. The more they investigated, the more suspicious they became. While some studies found that agents such as hydroxyethyl starch were effective, many others found evidence of harm associated with their use.

"Which study were we supposed to believe?" asks Zarychanski.

To find the answer, Zarychanski assimilated the results of every study on hydroxyethyl starch that had been completed in critically ill patients. A clear statistical pattern emerged. When all studies were considered, it became obvious that these products did more harm than good. Essentially, the study revealed, these products were killing people.

Through their work, Zarychanski and his seven-member team, which included three researchers from Winnipeg and four from other parts of Canada, determined that the signal for increased harm associated with hydroxyethyl starch was hidden in ostensibly favourable studies done by a scientist who had fabricated research results and performed experiments on people without proper ethical approvals. "When we excluded the results of trials performed by this discredited scientist, we found clear and irrefutable evidence that hydroxyethyl starch was causing death."

Specifically, Zarychanski's study of studies revealed that the use of hydroxyethyl starch - a product used around the world - increased the relative risk of death by seven per cent. "The critically ill patients who receive these types of products typically have a mortality rate of 25 to 50 per cent," says Zarychanski. "These patients already have a serious risk of dying. Prescribing a product that adds to this risk is most certainly bad medicine."

The importance and implications of Zarychanski's work was affirmed in February of this year when his study was published in the Journal of the American Medical Association. It generated media headlines around the world, and prompted the Winnipeg Health Region to issue a memo informing all physicians that hydroxyethyl starch was not to be used as a blood substitute for patients in need of blood volume expansion. Physicians who wish to use the product for other reasons will need to submit proof that it's beneficial and safe in these other applications, or else it will be withdrawn from the Region altogether. Influenced by Zarychanski's study, drug regulators in the United States and Europe are also reviewing the licensing permissions for hydroxethyl starch and other similar products.

In addition to raising awareness about the harmful effects of hydroxyethyl starch, the study and its subsequent publication has also underscored the importance of the work Zarychanski and his colleagues do at the CHI.

Established in 2008 with the support of a $2.5 million grant from Dr. George and Fay Yee, the CHI was designed to help the province's health-care system meet future challenges by becoming more innovative, flexible, responsive and proactive in its approach to providing services to a growing and aging population. The Knowledge Synthesis platform headed by Zarychanski is one of several key platforms at the heart of the centre's research mission. The other platforms are knowledge translation, system performance, clinical indicators, and research methods and statistical support. The CHI also has a Project Management Office that helps ensure the research produced at the centre is efficiently conducted and embraced by the health-care system.

At first glance, the idea of knowledge synthesis - scientifically reviewing studies to gain a true picture of the merits of a particular treatment, medication or procedure - may seem like a fairly straightforward proposition. But as the hydroxyethyl starch inquiry demonstrates, the practice of finding, reviewing and analyzing such studies is actually much more complicated.

"The aim of a knowledge synthesis review is to find all the information about a single question, to synthesize the data so they make sense, and then to present the results in a way that will inform clinical decision-making," says Zarychanski, 38, a native Winnipegger who, when not seeing patients or doing research, is an avid cross-country skier and road cyclist.

He offers an example to illustrate. "Imagine a scientific study that shows you can improve your survival from lung cancer if you're given a certain drug. If the drug is affordable and tolerable then it sounds like we should be using this drug, right?" But, more often than not, several studies exist that investigate the same drug for the same condition. "In the presence of multiple studies and conflicting results, which study do you believe? Do you believe the latest study, the biggest study or maybe the study that was done at your centre?" he asks. "How do we make a clinical decision or counsel a patient when multiple answers exist for a single question?" That's where the science - and art - of knowledge synthesis comes into play.

Although each platform at the CHI will play an integral part in making the healthcare system more efficient and responsive, the Knowledge Synthesis platform represents a major step forward for Manitoba's medical research community.

"Compared to the rest of the country, as Manitobans, we haven't yet contributed substantially to knowledge synthesis activities," says Zarychanski.

The Knowledge Synthesis platform at the CHI will help address this problem by creating a structure that will spur more research and by creating a venue for training others in the techniques of the discipline. The idea, says Zarychanski, is to build a team that will, very broadly, guide researchers, policy-makers and clinicalcare providers to make the best decisions possible. "If a systematic review or metaanalysis doesn't already exist, we will have the ability to produce one for ourselves," he says. "We will also be teaching others these methods so that researchers and policy makers in all domains can expand their abilities."

The Knowledge Synthesis platform launched the first class in systematic reviews and meta-analysis at the University of Manitoba in January. The course, taught by Zarychanski, Abou-Setta and Carol Friesen, a librarian at the University of Manitoba's Neil John Maclean Health Sciences Library, is available to graduate students (Masters and PhD), as well as existing researchers and practitioners.

This type of training is important, especially as investigators prepare funding applications for research projects. The ability to carry out systematic reviews - the heart of knowledge synthesis activities - is becoming an integral part of any successful research grant application. Increasingly, large research funding agencies expect a systematic review of a given topic to accompany a grant application, says Zarychanski. "Without this kind of analysis in grant proposals, would-be researchers will not be as competitive for funding, which means Manitoba-based research may not be prioritized nationally when compared to other provinces with entrenched capacity for systematic reviews and meta-analysis. The grant funders want to see this, and we will need to provide it," he says.

More successful research grants, of course, will lead to a larger research community, producing more important work that will expand the province's reputation as a centre for creating leading-edge medical knowledge. That, in turn, will help draw more experts to Manitoba to conduct research because they will know the province has a strong foundation with the proper supports in place - like the George and Fay Yee Centre for Healthcare Innovation - to help make them successful in their work.

The end result: better health care and a robust medical research community. The value of Zarychanski's work speaks for itself, says Dr. Terry Klassen, Academic Director of the George and Fay Yee Centre for Healthcare Innovation.

"With Ryan, we're very lucky to have someone of his calibre," says Klassen, who is also CEO and Scientific Director of the Manitoba Institute of Child Health and Associate Dean (Academic) and professor of Pediatrics and Child Health at the University of Manitoba's Faculty of Medicine.

"He's young and starting out, but already his work is having a huge impact. That just shows how fundamentally important knowledge synthesis is and how important it is to have Ryan leading this platform," says Klassen. "He's obviously very bright and becoming a leader in the field - and he's still taking care of patients."

Indeed, it was working with patients through his clinical practice that landed Zarychanski in the spotlight last year. He was part of a team that discovered the cause of a rare blood disease called hereditary xerocytosis, a type of anemia that causes red blood cells to have a shortened lifespan.

Interestingly, the condition was first identified about 40 years ago by the late Dr. Lyonel Israels, a former University of Manitoba researcher and founder of CancerCare Manitoba. Since then, scientists the world over had been trying to discover the cause of the disorder.

Zarychanski became involved after encountering a patient with the condition at the Centre for Blood Disorders Clinic at CancerCare Manitoba. He assembled a team of researchers, including a mentor of his, Dr. Donald Houston, and a medical student, Brett Houston (no relation). Together, they decided to arrange an unusual family meeting in order learn more about this disorder to obtain blood samples for further research.

"Part of providing adequate care to patients is understanding what is wrong with them. To study this family more carefully, we arranged a family reunion in a small town in Manitoba," he says. "We had about 150 of them attend. At the community centre we took histories, physicals and collected blood samples."

Eventually, Zarychanski and his team determined the disorder was caused by a genetic mutation in a type of protein that no one knew existed in red blood cells.

While the hydroxyethyl starch study published last February demonstrated the value of knowledge synthesis, it was not the first time Zarychanski had put the techniques to good use.

A few years ago, while attending university in Ottawa, he published a research paper on the use of a drug called erythropoietin (EPO), which can be used to increase red blood cell production. The drug has an infamous reputation because of its misuse by athletes in endurance sports like cross-country skiing and cycling to gain an unfair advantage over other competitors.

In the world of medicine, it was becoming increasingly common for critical care physicians to recommend patients receive EPO to boost their blood production and theoretically decrease the reliance on scarce blood donor resources.

"It was slowly becoming part of routine care in parts of North America and Europe - more so in the U.S. But I wasn't sure the practice was well justified and trial results were conflicting, so I completed a systematic review and analysis as part of a course I took to learn these very techniques," he says. "In the end, I was able to show that when you statistically combine all the studies, there is no benefit for patients, and a potential increase in complications."

Zarychanski found EPO saves about 0.4 units of blood per patient, but the product itself was expensive. "Essentially, it would cost millions (of dollars) to save one life if we continued to use this product," he says. "The take home message was this isn't worth the money. When the analysis was published in CMAJ (the Canadian Medical Association Journal), the practice of using EPO in critically ill patients essentially evaporated."

Zarychanski's work using knowledge synthesis techniques to improve hematological care for critically ill patients is far from finished.

He and his colleagues recently completed a systematic review of examining how best to provide massive blood transfusions to patients. This review led to a retrospective study on the care of severely bleeding patients in Manitoba.

With the help of the Project Management Office at the CHI, and in collaboration with Dr. Bryce Makar, an Emergency Department physician, and several individuals throughout the Winnipeg Health Region, Zarychanski examined the practice of providing blood transfusions at Health Sciences Centre.

The study revealed that it often takes too long to get blood to critically sick and injured patients in need of massive transfusions. In some cases, it took a few hours before all essential components of a transfusion were underway.

Now, Zarychanski and the Project Management Office at the CHI are implementing protocols and system changes that will quickly get blood to the patients who urgently need it. "Starting with Health Sciences Centre, we're now in the process of a comprehensive system overhaul. We will completely change the way we conduct massive transfusions, with the expectations of improving the survival of these patients," he says. This work is testimony to the powerful nature of knowledge synthesis, committed researchers, and the potential for clinical research to improve the lives of Manitobans. "The care we deliver to Manitobans is generally excellent, but we can always improve." he says.

Not only is knowledge synthesis helping change medical practices, Zarychanski says it's also helped guide some of his most recent clinical research.

For example, Zarychanski and Abou-Setta have just completed a systematic review and meta-analysis of a cheap blood thinner called heparin with a view to determining whether it should be used to reduce inflammation in patients with life-threatening infections. Their study shows that heparin might improve survival, but more research is needed.

"Based on the results of systematic review and two other preparatory studies, we are now conducting a pilot randomized clinical trial of heparin for critically ill patients in nine hospitals across Canada," he says.

If all goes well, Zarychanski and his team will conduct a large international trial of heparin in critically ill patients. If the results are positive then heparin, a cheap and widely available drug, will become part of routine care of patients with severe infections.

While Zarychanski has a number of projects underway, the work of the Knowledge Synthesis platform is really just beginning. He is hoping that a potential $20-million grant for the CHI will provide funds to expand the Knowledge Synthesis platform from two people to as many as 10.

The goal is to create a group that can help policy makers, researchers and clinicians plan and conduct systematic reviews and meta-analyses. "A surgeon or hospital administrator can come to us saying, 'I've got an important question that needs an answer; are you able to assist?' We can bring researchers, methodology experts, and content experts together who will create a capacity to answer these questions," he says.

Before the CHI was launched, the province did not have a group of researchers dedicated to answering these questions using this specific type of research methodology.

"Now we have the ability to be self-sufficient and answer our own clinical questions - those that are particularly important for Manitobans," he says. "Tools such as systematic reviews can identify research needs and, ultimately, we can set out on big changes that will improve, and even save, the lives of patients in the province and elsewhere."

Joel Schlesinger is a Winnipeg writer.

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Fostering ingenuity

The George and Fay Yee Centre for Healthcare Innovation supports leading edge medical research

It's difficult to put a price tag on well-being, but in Canada, one thing is certain: the cost of providing health care is rising.

And according to a recent report by the Canadian Institute for Health Information, expenses to deliver care will continue to climb as the population becomes older, on average, because more people will require more care.

Yet government budgets are becoming tighter at the same time. As a result, innovation is increasingly seen as the solution to meeting future health-care challenges.

It's for that reason the George and Fay Yee Centre for Healthcare Innovation (CHI) was created, says Dr. Terry Klassen, Academic Director of the centre.

"We're all proud of our Canadian health-care system, but there are a lot of stresses and concerns about the system's sustainability. One way to alleviate those problems is through innovation," he says. "The vision is to have this centre embedded both in the Winnipeg Health Region and in the University of Manitoba so we can take the brightest researchers producing new knowledge and implement those innovations to provide the best care with limited resources."

The centre received a $2.5 million dollar donation from Dr. George and Fay Yee in 2008. Yee is a pathologist who graduated from the University of Manitoba in 1960, and now has a successful pathology practice and laboratory in Windsor, Ontario.

"Their donation was the catalyst to get this whole thing going," Klassen says.

Since its start, the centre's central aim has been to facilitate knowledge from bench to bedside, ensuring the best practices become policy, and guide highlevel decision-making toward long-term sustainability of the health-care system. In other words, it is designed to help physicians and other health-care providers make better decisions with their patients.

"Health is at its core a knowledge industry so the explosion in research and new knowledge has meant that it's really hard for any one person to keep track of all that's going on," says Klassen.

"Some people estimate the average family doctor would have to read 19 scientific articles every day just to keep on top of all the new findings."

That's where the centre's units of research and practice teams come into play. Take knowledge synthesis, for example.

"People often say that good, clean knowledge is almost like the revolution back when John Snow discovered the need for clean water and, of course, that really limited disease back then," he says. "Today it's the need for clean knowledge that really drives the health-care system to make the right decisions."

To help lead this revolution in Manitoba, the centre has identified foundational platforms, some of which include:

Knowledge Synthesis

This is the discipline of studying the studies, so to speak, in which researchers examine all of the medical research in a particular area, sorting the good from the bad.

Knowledge Translation

New research that can improve care is emerging every day, but just because it's useful doesn't necessarily mean it will actually reach the bedside. Knowledge Translation aims to ensure the province's leading researchers' work doesn't just remain in the lab and medical journals and is instead used to enhance the delivery of health care.

System Performance and Measurement

Looks at how different parts of the system function, how efficiently care is delivered and how to achieve the best outcomes for patients. For example, team leader Dr. Eric Bohm, an orthopedic surgeon and assistant professor in the Department of Surgery at the University of Manitoba's Faculty of Medicine, is examining how best to repair hip fractures and reduce wait times for surgical care.

Research and Evaluation

This team brings expertise in evaluating health programs, conducting community health assessments, analyzing and interpreting studies and has strong links to decision makers in the Region.

Data Science

This group includes biostatisticians, epidemiologists, computational biologists and analysts who will uncover new findings that will transform patient care.

Project Management Office

The PMO is charged with ensuring the work done at the CHI becomes part of the Region's every day practices. The PMO, initially established by the Winnipeg Health Region, was recently embedded within the CHI.

Klassen says the addition of the Project Management Office is significant. "This arm of the (Region) has a good reputation for the implementation of projects," Klassen says. "The fact that it's not located somewhere else is very a very powerful sign" of the Region's commitment to supporting the George and Fay Yee Centre for Healthcare Innovation.

In fact, its integration within the centre has earned it accolades from national funding agencies, he says. "When we presented this in Ottawa to the Canadian Institutes for Health Research (CIHR), a leading provider of research funding in Canada, they were just blown away by what we've created and what we've been able to accomplish so far."

Klassen says the hope is that a good first impression will lead to more research dollars for the centre's future endeavours.

"We have a $20 million proposal to fund the centre for the next five years," he says. "We have matching funding from the province and the university to the tune of $10 million, and we're hoping that the CIHR will provide the other $10 million."

Klassen says he's very optimistic about the Centre for Healthcare Innovation's future and impact on care in Manitoba and Canada because it has been a leadingedge medical knowledge facilitation centre in Canada from its inception.

"We probably have the best alliance between health region and university, and so, a lot of the fundamentals are lining up," he says. "(The CHI) will transform the way we provide health care and I think we could be the envy of the country in terms of this kind of targeted research."

Here are some of the projects underway or completed at the George and Fay Yee Centre for Healthcare Innovation:

Cataract Wait Times Assessment

As Manitoba's population ages, the demand for cataract surgery continues to grow. This project, started in 2012, is designed to help reduce wait times for cataract surgery while ensuring services are delivered efficiently. A key element of the design involves providing patients with choice when booking cataract surgeries.

Virtual Ward

One of the major barriers to effective patient flow in Emergency Departments are patients who suffer from chronic illness and deterioration in functional status, but have been medically cleared and suffer no acute illness. The virtual ward project identifies patients who are at high risk of acute service use and coordinates all aspects of their care within the patients' home. As a result, presentations to Emergency for the pilot group were reduced by 58 per cent with a 50 per cent decrease in hospital inpatient days.

First Nations Community Based Screening to Improve Kidney Health and Prevent Dialysis

This three-year project, funded by Health Canada through the Health Services Integration Fund, will provide kidney disease screening in First Nations communities. The goal of the project is to reduce the rate of kidney disease and the need for dialysis.

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Dr. Ryan Zarychanski

Born and raised in Winnipeg, Dr. Ryan Zarychanski completed his residency in internal medicine and subspecialty fellowships in critical care medicine and hematology at the University of Manitoba. He received a Master's degree in epidemiology and community medicine as well as a research fellowship at the University of Ottawa.

He now works as a clinician scientist at CancerCare Manitoba and the University of Manitoba in the Department of Internal Medicine, Sections of Critical Care and Hematology/Medical Oncology. He is also Director of the Knowledge Synthesis platform at the George and Fay Yee Centre for Healthcare Innovation.

Hospital and Academic Appointments

2009 to present: Assistant Professor, Department of Internal Medicine and the Department of Community Health Sciences, University of Manitoba

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